The gammaherpesviruses establish lifelong latency in the human host. Kaposi's sarcoma-associated herpesviruses (KSHV) and Epstein-Barr Virus (EBV) are members of this family. These viruses are associated with several different cancers in the human population, are present in the oral cavity, and can be transmitted orally. The gammaherpesviruses establish life-long latency in the host. During latency the viral genome is chromatinized by host factors, and viral gene expression is extremely limited during latency. However during viral reactivation, many of the chromatin modifications are changed resulting in the transcription and expression of many more viral genes. We have recently performed a siRNA screen and identified a novel cellular kinase, tousled like kinase (TLK) that is involved in regulating the gammaherpesviral latent-lytic switch and modulating the host genome. In response to RFA-DE-13-002, we propose to understand how TLK regulates the viral epigenome to augment latency and suppress reactivation. Understanding of the mechanism involved in governing gammaherpesviral latency and reactivation is relevant to oral cancer and oral disease associated with replication of these viruses. Our investigation may help guide novel therapies for treatment of oral disease.